PROJECT SUMMARY Zika virus (ZIKV) is a flavivirus that is currently spreading throughout the Americas at such a rate that the World Health Organization has declared this a public health emergency of international concern. ZIKV is particularly dangerous among women since infection during pregnancy has been associated with fetal abnormalities including microcephaly and severe neurological disorders. Although a handful of vaccine candidates are under different stages of evaluation, there is no licensed vaccine available to combat this epidemic. Previously, we have developed inactivated vaccines that have shown efficacy in a number of preclinical models and in particular, protection against other flavivirus-associated diseases such as West Nile virus encephalitis and viscerotropic yellow fever. Here, we provide preliminary data on an advanced ZIKV vaccine candidate that induces strong neutralizing antibody responses against geographically distinct strains of ZIKV and protects against lethal disease in an immunodeficient mouse model. Based on these promising results, we have assembled a team of investigators with the expertise and resources necessary to prepare clinical-grade ZIKV vaccine suitable for Phase I trials. This project incorporates many of the essential vaccine development goals listed in RFA-AI-16-034 including evaluation of safety, toxicity, and immunogenicity; evaluation of efficacy in appropriate challenge models; optimization of production methods/process development; quality assurance/quality controls for analysis and characterization of vaccine components including purification, identity, and stability at optimal and elevated storage temperatures; and cGMP-compliant manufacturing of vaccine material suitable for completing all applicable IND-enabling preclinical studies. Upon completion of these objectives, we will have cGMP-grade vaccine material suitable for initiation of Phase I clinical trials and an opportunity to reduce the burden of ZIKV-associated disease and infant microcephaly.